Monday, July 21, 2008

An editorial published in the BMJ on Friday ,claims (the editorial is by Jane J Kim, assistant professor of health decision science Program in Health Decision Science, Department of Health Policy and Management, Harvard School of Public Health, Boston, MA 02115, USA) that the UK government may save 18.6 million pounds ($37 million) annually as a result of its decision to select GlaxoSmithKline's ( a UK based pharma company) cervical cancer vaccine Cervarixfor its human papillomavirus immunisation programme rather than Merck & Co.'s (a US basd pharma company) and Sanofi-Aventis' ( a Paris, France based company) Gardasil.(Search this site on "Gardasil" for post on the subject)

The model involves 34 variables (Table 1) about which assumptions are made as rationally as possible on the available evidence (We then generated parameter values for cost and utility weights by Monte Carlo sampling (using the Latin hypercube method) from the joint distribution of plausible ranges of values for each parameter - which sounds impresive but is in reality a sort of re-inforced guess, as so litle actual evidence of use is currently available). To make a detailed evaluation of the methodolgy and the evidence supporting the assumptions is skilled and complicated task. Such modelling can easily be "tweaked" ... "We constructed a total of 2700 possible scenarios " . A stricture used is that users of such Monte Carlo simulations rely entirely on the initial subjective estimates and almost never follow up with empirical observation.i.e they place over reliance on the model.. which they have to because no more empirical evidence is available currently.

Faced with a need to make a decsion within a timeframe these limitations must be accepted - however we have the luxury of time, a delay in decsion making makes the position no worse and affords time to refine procedures, undertake critical analysis and consult other viewpoints.

"Only the 72% of model structures that best fit prevalence data for human papillomavirus were used in the analysis, but care should be taken when interpreting model results not to assume that each of the remaining model structures is equally plausible. etc., etc., caveat, caveat ...."

"Although we have included the estimated impact of screening in the model and tried to account for the accuracy of screening in our results, some of the details of the programme (such as rescreening women more often after a suspect result) are difficult to properly implement in the current model structure."

The conclusion arrived at was that Vaccinating 12 year old schoolgirls with a quadrivalent (protection against 4 known HPV virus' 2 of which cause genital warts) vaccine at 80% coverage is likely to be cost effective at a willingness to pay threshold of £30 000 ( Euros 37 700; $59 163) per QALY gained (quality adjusted life years (QALYs), discounted costs and benefits at 3.5% per year in the base case, and adopted a healthcare provider perspective on costs, as required by the National Institute for Health and Clinical Excellence), if the average duration of protection from the vaccine is more than 10 years.

Implementing a catch-up campaign of girls up to age 18 is likely to be cost effective.

Vaccination of boys is unlikely to be cost effective.

A bivalent vaccine (affording protection against HPV virus' that cause cervical cancer NOT genital warts) with the same efficacy against human papillomavirus types 16 and 18 costing £13-£21 less per dose (this is max. 10% of vaccine costs) (depending on the duration of vaccine protection) may be as cost effective as the quadrivalent vaccine although less effective as it does not prevent anogenital wartsJane Kim in the editorial said that "the decision to select the bivalent vaccine implies the Department of Health is willing to accept foregone health benefits (and additional cost savings) from averting cases of genital warts for the reduced financial outlay."

Jane Kim added: "Assuming 80-percent coverage of current 12-year-old girls (each year cohort has some 350,000 girls) in the UK with the full three-dose vaccine series, this price differential translates to savings of 11.5 million pounds ($23 million) to 18.6 million pounds ($37 million) from the vaccine price alone in the first year of the programme.”

In response, a spokesperson for the Department of Health noted that "the contract has been awarded for the vaccine that scored best overall against a number of pre-agreed criteria and offers best value overall to the NHS."

This policy of limited protection at a reduced costs is not without its critics. Colm O'Mahony, a consultant in sexual health at Chester Foundation Trust, commented that “all the clinical evidence pointed to Gardasil and instead [the government has] chosen a vaccine suitable for the Third World.”

Natika Halil, director of information at the Family Planning Association, remarked that "genital warts has its own financial cost to the NHS which spends 22 million pounds ($44 million) a year treating it, so it will be interesting to see how this has been factored into the cost analysis.”

As part of the cost analysis it was intersting to note that the NHS accept that the basic pap smear at Pap smear (£21.70, 2002 prices) is less than the recently introduced liquid based cytology (£25.40, 2003 prices). Also Costs for screening at sexual health clinics and outpatient clinics are higher (£37 and £68 respectively, 2003 prices). These costs will not diappear because screening will still be required because the vaccine only affords protection against 70% of potential HPV strains.

GlaxoSmithKline stated that data on Cervarix have demonstrated the prevention of pre-cancerous lesions and a strong immune response for 6.4 years, noting that “this is the longest duration of protection reported for any vaccine against HPV 16 and 18.”

The government's vaccination programme in 12-year-old girls is expected to start in September.

The Department of Health has released Press release today "300,000 more girls to be offered vaccine against Cervical cancer - extension of the HPV vaccination progamme ". This trumpets the decision to choose Cervarix at a lower cost - for a routine vaccination of girls 12-13 years old starting in September which it is claimed will eventually save up to 400 lives for each year of girls receiving the vaccine. As a consequence The national vaccination programme against HPV is being extended to offer protection to an additional 300,000 girls aged 17-18, starting in September.

A 2 year ‘catch-up programme’ will start in the school year 2009/10 to vaccinate girls aged between 15 to 18. Today’s announcement means that girls, who would not otherwise have been included in this catch-up programme, will now be vaccinated this school year. Boys will not be vaccinated at any age.

Dawn Primarolo says the cost of the vaccine is commercially confidential. Cervarix® will be purchased by the Department of Health who will supply it free of charge to the NHS.

The financial consequences will be that The Department of Health will provide additional support to PCTs in guidance and funding to ensure that the roll out of the older cohort is a success.

There will be an additional £10 million for PCTs in the 2008/09 financial year to implement this extra programme.

It is not accidental or incidental that programme on Channel 4 Dispatches (in the UK only), "The Jab that can stop Cancer" presented by Jane Moore (who has paid privately for the vaccine for one of her daughters and will eventually for the younger daughter to have Gardasil) will discuss this subject at 8.pm this evening.

Professor David Salisbury , Director of Immunisation,Dept. of Health made great claims for the precision of the modelling and calculation for costs and benefits - making asinine remarks about the amount of computer time spent in running the models - all weekend, when nobody else was using it - as if that was proof of veracity or accuracy.

A lady epidemiologist pointed out that cervical cancer rates and mortality had fallen dramatically since pap screening was introduced and that 40 wome died per million. She queried whether the costs justified he claimed benefits say against the people who will suffer heat diseases or more common life threatening cancers.

A snapshot was also provided how the UK market was softened u by intensive (and dubious) marketing programs, and thiny veiled surveys paid for by the pharma companies were presented to the press as "evidence".

GP's , now used a better educated and better informed patient were asking for protection for their children- simply assuming the benefits it provided on the wave of "astro-turfing" or the unquestioning and incurious wall to wall press coverage.

No mention was made of the details of the modelling, nor was it made clear that Cervarix provides no protection against other HPV strains ( are over 100 known strains) that cause genital warts - nor was the case examined for protecting boys.

In the world of private medicine, Jane Moore has made her decision , US and French (and those in 100 countries where it is currently approved) citizens will make theirs (although different insurers have different policies)

As the NHS / Government have made a decision to supply at no extra cost the parent has to first consider ;1. Any vaccine carries risks when used, what are those risks ?To date the only large scale usage has been in the US and we posted about the latest report here Tuesday, July 08, 2008 Gardasil® gets 7,802 adverse reports to CDC by VAERS system

2. Having accepted that risk , what risk is there of my daughter eventually coming in contact with a strain of HPV ?

It is not 100% but near it. The more promiscuous (ie the greater number of sexual partners - of either sex, it can be transmitted between women) she is, the greater the chance. There is no clear evidence that sexually transmitted infections (STI) have any effect on increasing / reducing the impact. Please note that the cervical smear test, whilst it will may discover evidence of STI's , that information in the UK will not be passed on to the patient. It is not a genito urinary test. (As an aside it would be a service to women to re-jig the test to incorportate a genito - urinary test)

The "pap" smear testing will continue (remember that results vary regionally, and are reported differently, the NI method of identification is different to the rest of the UK. The report also identiffies that fact that over time it will be necessary ..." to take account of possible changes to the cervical screening programme, such as the introduction of DNA testing for human papillomavirus, .....It is clear that significant further work on the design of optimal screening and vaccination programmes is required, particularly if the introduction of vaccination accelerates the recent trend for the declining uptake of screening.

i.e it is possible (many would say highly likely) that vaccination will lead to lack of detection in the population as women will think or assure themselves that the unpleasant cervical smear routine can be avoided.

The FDA says the human papillomavirus is the most common sexually transmitted infection in the U.S. The Centers for Disease Control and Prevention estimates that about 6.2 million Americans become infected with genital HPV each year and that more than half of all sexually active men and women become infected at some time in their lives.

3. If she contracts an HPV will it be oncogenic (cause cervical cancer) ?Currently it is felt that the 2 strains afforded protection by both current vaccines accounts for 75-80% of HPV's discovered in pap tests.

Of women conracting oncogenic lesions, the eventual death rate some 40 per 1 Mn a year die, many of course suffer an unpleasant and debilitating illnes for varying periods like all cancers.

4. Will better vaccines become available affording more protection ... ?

No doubt other manufacturers are working , and GSK and Merck will be improving their product - it must be assumed newer products will afford better protection and less risk at lower cost. The timescale is unknown.

To be effective protection must be given prior to any sexual contact - it is not necessary for intercourse to take place for transmission.

This site does not give medical advice, it gives plenty of information and directs the user to sources of further information. Anyone considering having their children vaccinated for HPV must consult their GP.

Joe Moore chose it for her children.

Lord Patel is ;

1. Very sceptical of the need to make a decision - there is no urgency.

2. Not at all impressed by Dr David Sainsbury Salisbury and his fancy modelling - truly it is as good as modern techniques and the data available can provide. The assumptions / guesses used are not based on sufficiently strong evidence .. yet, more will become available as others users / providers take part in a very large experiment on their children. Lord Patel can see no reason why anyone should enter their children in this great experiment. Giving you children a healthy diet, exercise and making sure they never smoke are far greater benefits you can pass on to your kids.3. Feels that the NHS has higher priorities than providing at zero cost a protection which in essence will stimulate promiscuity rather than restrict it - with the attendant risks of STI's.

4. Is certain that undue pressure (without any proof, but based on wide experience of big pharma) has been put on the decision makers to support a "British" product.

5. It also represents another example of the state usurping personal choices and decisions using a decision making process which is opaque to many people - inlcuding most of the medical profession. (next time you see your GP ask him about the Monte Carlo method usng tjhe latin hypercube method)

You would indee be correct in identifying the deliberate mistake whch even the profroaders mist.

Since posting above, our vast team of statisticians and mathematical modellers have had the opportunity to discuss this with a statistician who we trust implicitly who has wide and extensive knowledge of modelling for pharmaceutical applications.

Apart from being scathing about health econonomics modelling he exprsssed rservations about -1. Need to make a decision2. How anyone making such a decision can ignore the vast and detailed results of over 20 millon doses used in the US and the resulting reporting of adverse effects.3. The limited attempts at considering 2ndary inter actions of variables known and variables unknown (eg do genital warts inrease chances of transmission ?). Such attempts would of course be hungry for Dr D S's working over the weekend but there shoudl at least be some attempt to at least consider them4. They were in agreement that this constitutes a vast experiment on 350,000 schoolchildren for negligible benefits in terms of public health over a period of at least 6 decades. There are some more urgent matters to consider in medical treatments and gave the example of the Use of Statins.5. Agreed that the end result was surprisingly jingoistic, especially in the fact that protection against genital warts had been ignored.

Whilst unsightly and hitherto considered a more aesthetic than a medical problem, the topical treatment (freezing, cutting away, chemical trreatment) of them is a major element of Genito Urinary work.

Just in time the annual STI results are out ...Sunderland Echo for exmple extracts the details for Geordie lads'n'lassies.

Statistics released by the Health Protection Agency (HPA) reveal that although young adults represent only 13% of the region's population, they are most at risk of being diagnosed with a sexually transmitted infection.

Research shows that the North East's 16 to 24-year-olds accounted for 73% of chlamydia, 64% of genital warts and 50% of gonorrhoea infections diagnosed in genito-urinary medicine (GUM) clinics last year.

Across all age groups, the number of new sexually transmitted infections (STIs) diagnosed in the North East in 2007 increased by 8% on the previous year.